The clinical advantage of APG-2575 is beginning to appear, the first domestic Bcl-2 inhibitor for CLL/SLL has unlimited prospects

On June 7, 2021, Ascent Pharmaceuticals presented an oral report on the latest clinical progress of the new generation of Bcl-2 inhibitor APG-2575 at the ASCO meeting.
Among 15 patients with R/R CLL/SLL, 12 cases achieved partial remission ( PR), the overall response rate ORR is as high as 80.
0%
.

In terms of safety, no dose-limiting toxicity (DLT) was observed at 1200 mg, and no tumor lysis syndrome occurred

Ascend medicine ASCO

Bcl-2 target

Bcl-2 target Bcl-2 target

Bcl-2 family proteins are divided into three categories: the first category is proteins that inhibit cell apoptosis, such as Bcl-2, Mcl-1, and Bcl-xL; the second category is proteins that promote apoptosis, such as Bak, Bax and the like; last category of pro-apoptotic BH3 domain-containing proteins such as Bad, Puma and the like
.

Bcl-2, Mcl-1 and Bcl-xL play an important role in tumorigenesis and metastasis, and thus become important potential therapeutic targets

Iterative development process of Bcl-2 inhibitors

Iterative R&D Process of Bcl-2 Inhibitors Bcl-2 Inhibitor Iterative R&D Process

Early Bcl-2 preparations focused on multiple targets, while inhibiting Bcl-2, Bcl-xl, Bcl-w and so on
.

Due to the functional redundancy of these types of proteins, theoretically selective inhibition of a certain protein may not be able to effectively exert anti-tumor effects

When these multi-target Bcl-2 inhibitors entered the clinic, they were found to have strong platelet toxicity.
Subsequent studies found that Bcl-xl was highly expressed on platelets, so non-selective Bcl-2 inhibitors could not be achieved due to platelet toxicity.
The effective treatment window can only be used in clinics by reducing the dose and adopting methods such as combination therapy
.

Further studies by AbbVie and Genentech have found that Bcl-2 specific ABT-199 has good anti-tumor activity against many hematomas
.

This indicates that although functional redundancy exists, some hematomas are still highly dependent on Bcl-2

FDA

Due to different mechanisms of action, Bcl-2 inhibitors can be combined with a variety of drugs to enhance anti-tumor activity
.

For example, Venetoclax is developing a variety of combination therapies, including BTK inhibitor combination, CD20 antibody rituximab combination, azacitidine/decitabine combination, bortezomib/dexamethasone combination, etc.

Yasheng Pharmaceutical: Pioneer in the research and development of Bcl-2 inhibitors

Ascent Pharmaceuticals: Pioneer in the research and development of Bcl-2 inhibitors

Yasheng Pharmaceuticals Yang Dajun and Wang Shaomeng have been committed to the research and development of Bcl-2 inhibitors since 2003
.

Yang Dajun and Wang Shaomeng quickly screened the natural product derivative AT-101, which also targets Bcl-2, Mcl-1, and Bcl-xL , and is effective in oral administration.

Bcl-2, Mcl-1, Bcl-xL

At the same time, Yasheng Pharmaceutical began to develop selective and dual-target Bcl-2 inhibitors
.

APG-1252 targets Bcl-2 and Bcl-xl, and solves the problem of platelet toxicity in the early development process; APG-2575 selectively targets Bcl-2, and its PK/PD characteristics determine that it can achieve better safety

Pre-clinical studies have shown that APG-2575 and BTK inhibitors have significant synergistic anti-tumor activity, and the clinical development of combined therapy is full of great potential
.

The combination of APG-2575 and MDM2-p53 inhibitor APG-115 in the treatment of DLBCL also showed significant synergistic anti-tumor activity
.

 

to sum up

Summary summary

APG-2575 has excellent efficacy in the early clinical data of R/R CLL/SLL, which is comparable to AbbVie's Venetoclax, and is also comparable to the efficacy data of BTK inhibitors
.

More importantly, Bcl-2 inhibitors and BTK inhibitors are not purely competitive.

As the second Bcl-2 selective inhibitor in the world and the first domestically to enter the clinical stage, APG-2575 has outstanding clinical effectiveness and safety, and has the potential to become a best-in-class (Best-in-class)
.

In addition to the domestic leading position of Yasheng Pharmaceutical in the new generation of Bcl-2 selective inhibitors, BeiGene BGB-11417 and Nuocheng Jianhua ICP248 are also actively advancing, looking forward to the follow-up clinical progress of this target in China
.

references

References References

• A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma (2020);

• Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives (2021);

• Therapeutic development and current uses of BCL-2 inhibition (2020);

• Anti-apoptotic BCL-2 family members in development (2018);

• Targeting the Bcl-2 Family in B Cell Lymphoma (2019)
  .
  

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma (2020);

A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma (2020);

Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives (2021);

Targeting BCL-2 in Cancer: Advances, Challenges, and Perspectives (2021);

Therapeutic development and current uses of BCL-2 inhibition (2020);

Therapeutic development and current uses of BCL-2 inhibition (2020);

Anti-apoptotic BCL-2 family members in development (2018);

Anti-apoptotic BCL-2 family members in development (2018);

Targeting the Bcl-2 Family in B Cell Lymphoma (2019)
.

Targeting the Bcl-2 Family in B Cell Lymphoma (2019)
.

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